Specificity of Pitx3-Dependent Gene Regulatory Networks in Subsets of Midbrain Dopamine Neurons.
Identifieur interne : 000148 ( PubMed/Checkpoint ); précédent : 000147; suivant : 000149Specificity of Pitx3-Dependent Gene Regulatory Networks in Subsets of Midbrain Dopamine Neurons.
Auteurs : Panojot Bifsha [Canada] ; Aurelio Balsalobre [Canada] ; Jacques Drouin [Canada]Source :
- Molecular neurobiology [ 1559-1182 ] ; 2016.
Abstract
Dysfunction of midbrain dopaminergic (mDA) neurons is involved in Parkinson's disease (PD) and neuropsychiatric disorders. Pitx3 is expressed in mDA neuron subsets of the substantia nigra compacta (SNc) and of the ventral tegmental area (VTA) that are degeneration-sensitive in PD. The genetic network(s) and mode(s) of action of Pitx3 in these mDA neurons remain poorly characterized. We hypothesized that, given their distinct neuronal identities, Pitx3-expressing neurons of SNc and VTA should differ in their Pitx3-controlled gene expression networks and this may involve subset-specific co-regulators. Expression profiling of purified mDA neuronal subsets indicates that Pitx3 regulates different sets of genes in SNc and VTA, such as activating the expression of primary cilium gene products specifically in VTA neurons. Interaction network analysis pointed to the participation of differentially expressed Lhx/Lmo family members in the modulation of Pitx3 action in SNc and VTA mDA neurons. Conversely, global binding patterns of Pitx3 on genomic DNA of human dopaminergic cells revealed that Pitx3 is often co-recruited to regions that foster the formation of GATA-bHLH-BRN complexes, which usually involve Lmo co-regulatory proteins. We focused on Lmo3 for its preferential expression in SNc neurons and demonstrated that it functions as a transcriptional co-activator of Pitx3 by enhancing its activity on genomic regulatory elements. In summary, we defined the SN and VTA-specific programs of Pitx3-dependent gene expression and identified Lmo3 as a SN-specific co-regulator of Pitx3-dependent transcription.
DOI: 10.1007/s12035-016-0040-y
PubMed: 27514757
Affiliations:
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xml:lang="fr">Canada</country><wicri:regionArea>Laboratoire de génétique moléculaire, Institut de recherches cliniques de Montréal (IRCM), 110, avenue des Pins Ouest, Montréal, Québec, H2W 1R7</wicri:regionArea><wicri:noRegion>H2W 1R7</wicri:noRegion></affiliation></author><author><name sortKey="Drouin, Jacques" sort="Drouin, Jacques" uniqKey="Drouin J" first="Jacques" last="Drouin">Jacques Drouin</name><affiliation wicri:level="1"><nlm:affiliation>Laboratoire de génétique moléculaire, Institut de recherches cliniques de Montréal (IRCM), 110, avenue des Pins Ouest, Montréal, Québec, H2W 1R7, Canada. jacques.drouin@ircm.qc.ca.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Laboratoire de génétique moléculaire, Institut de recherches cliniques de Montréal (IRCM), 110, avenue des Pins Ouest, Montréal, Québec, H2W 1R7</wicri:regionArea><wicri:noRegion>H2W 1R7</wicri:noRegion></affiliation></author></analytic><series><title level="j">Molecular neurobiology</title><idno type="eISSN">1559-1182</idno><imprint><date when="2016" type="published">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Dysfunction of midbrain dopaminergic (mDA) neurons is involved in Parkinson's disease (PD) and neuropsychiatric disorders. Pitx3 is expressed in mDA neuron subsets of the substantia nigra compacta (SNc) and of the ventral tegmental area (VTA) that are degeneration-sensitive in PD. The genetic network(s) and mode(s) of action of Pitx3 in these mDA neurons remain poorly characterized. We hypothesized that, given their distinct neuronal identities, Pitx3-expressing neurons of SNc and VTA should differ in their Pitx3-controlled gene expression networks and this may involve subset-specific co-regulators. Expression profiling of purified mDA neuronal subsets indicates that Pitx3 regulates different sets of genes in SNc and VTA, such as activating the expression of primary cilium gene products specifically in VTA neurons. Interaction network analysis pointed to the participation of differentially expressed Lhx/Lmo family members in the modulation of Pitx3 action in SNc and VTA mDA neurons. Conversely, global binding patterns of Pitx3 on genomic DNA of human dopaminergic cells revealed that Pitx3 is often co-recruited to regions that foster the formation of GATA-bHLH-BRN complexes, which usually involve Lmo co-regulatory proteins. We focused on Lmo3 for its preferential expression in SNc neurons and demonstrated that it functions as a transcriptional co-activator of Pitx3 by enhancing its activity on genomic regulatory elements. In summary, we defined the SN and VTA-specific programs of Pitx3-dependent gene expression and identified Lmo3 as a SN-specific co-regulator of Pitx3-dependent transcription.</div></front></TEI><pubmed><MedlineCitation Status="Publisher" Owner="NLM"><PMID Version="1">27514757</PMID><DateCreated><Year>2016</Year><Month>08</Month><Day>12</Day></DateCreated><DateRevised><Year>2016</Year><Month>08</Month><Day>12</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1559-1182</ISSN><JournalIssue CitedMedium="Internet"><PubDate><Year>2016</Year><Month>Aug</Month><Day>11</Day></PubDate></JournalIssue><Title>Molecular neurobiology</Title><ISOAbbreviation>Mol. Neurobiol.</ISOAbbreviation></Journal><ArticleTitle>Specificity of Pitx3-Dependent Gene Regulatory Networks in Subsets of Midbrain Dopamine Neurons.</ArticleTitle><Pagination><MedlinePgn></MedlinePgn></Pagination><Abstract><AbstractText>Dysfunction of midbrain dopaminergic (mDA) neurons is involved in Parkinson's disease (PD) and neuropsychiatric disorders. Pitx3 is expressed in mDA neuron subsets of the substantia nigra compacta (SNc) and of the ventral tegmental area (VTA) that are degeneration-sensitive in PD. The genetic network(s) and mode(s) of action of Pitx3 in these mDA neurons remain poorly characterized. We hypothesized that, given their distinct neuronal identities, Pitx3-expressing neurons of SNc and VTA should differ in their Pitx3-controlled gene expression networks and this may involve subset-specific co-regulators. Expression profiling of purified mDA neuronal subsets indicates that Pitx3 regulates different sets of genes in SNc and VTA, such as activating the expression of primary cilium gene products specifically in VTA neurons. Interaction network analysis pointed to the participation of differentially expressed Lhx/Lmo family members in the modulation of Pitx3 action in SNc and VTA mDA neurons. Conversely, global binding patterns of Pitx3 on genomic DNA of human dopaminergic cells revealed that Pitx3 is often co-recruited to regions that foster the formation of GATA-bHLH-BRN complexes, which usually involve Lmo co-regulatory proteins. We focused on Lmo3 for its preferential expression in SNc neurons and demonstrated that it functions as a transcriptional co-activator of Pitx3 by enhancing its activity on genomic regulatory elements. In summary, we defined the SN and VTA-specific programs of Pitx3-dependent gene expression and identified Lmo3 as a SN-specific co-regulator of Pitx3-dependent transcription.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Bifsha</LastName><ForeName>Panojot</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>Laboratoire de génétique moléculaire, Institut de recherches cliniques de Montréal (IRCM), 110, avenue des Pins Ouest, Montréal, Québec, H2W 1R7, Canada.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Division of Experimental Medicine, McGill University, Montréal, Quebec, H3A 1A3, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Balsalobre</LastName><ForeName>Aurelio</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Laboratoire de génétique moléculaire, Institut de recherches cliniques de Montréal (IRCM), 110, avenue des Pins Ouest, Montréal, Québec, H2W 1R7, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Drouin</LastName><ForeName>Jacques</ForeName><Initials>J</Initials><Identifier Source="ORCID">http://orcid.org/0000-0001-8226-5691</Identifier><AffiliationInfo><Affiliation>Laboratoire de génétique moléculaire, Institut de recherches cliniques de Montréal (IRCM), 110, avenue des Pins Ouest, Montréal, Québec, H2W 1R7, Canada. jacques.drouin@ircm.qc.ca.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Division of Experimental Medicine, McGill University, Montréal, Quebec, H3A 1A3, Canada. jacques.drouin@ircm.qc.ca.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2016</Year><Month>08</Month><Day>11</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Mol Neurobiol</MedlineTA><NlmUniqueID>8900963</NlmUniqueID><ISSNLinking>0893-7648</ISSNLinking></MedlineJournalInfo><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">Lmo3</Keyword><Keyword MajorTopicYN="N">Parkinson</Keyword><Keyword MajorTopicYN="N">Primary cilium</Keyword><Keyword MajorTopicYN="N">Substantia nigra</Keyword><Keyword MajorTopicYN="N">Ventral tegmental area</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2016</Year><Month>03</Month><Day>10</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2016</Year><Month>08</Month><Day>05</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2016</Year><Month>8</Month><Day>13</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2016</Year><Month>8</Month><Day>16</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2016</Year><Month>8</Month><Day>16</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>aheadofprint</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">27514757</ArticleId><ArticleId IdType="doi">10.1007/s12035-016-0040-y</ArticleId><ArticleId IdType="pii">10.1007/s12035-016-0040-y</ArticleId></ArticleIdList></PubmedData></pubmed><affiliations><list><country><li>Canada</li></country></list><tree><country name="Canada"><noRegion><name sortKey="Bifsha, Panojot" sort="Bifsha, Panojot" uniqKey="Bifsha P" first="Panojot" last="Bifsha">Panojot Bifsha</name></noRegion><name sortKey="Balsalobre, Aurelio" sort="Balsalobre, Aurelio" uniqKey="Balsalobre A" first="Aurelio" last="Balsalobre">Aurelio Balsalobre</name><name sortKey="Drouin, Jacques" sort="Drouin, Jacques" uniqKey="Drouin J" first="Jacques" last="Drouin">Jacques Drouin</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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